Tuesday, May 26, 2009

Tablet Technology

Tablet Technology Presses On

Near infrared analysis methods can be used to check in-process quality on rotary tablet presses.

Long considered to be somewhat recession-proof, the pharmaceutical industry has certainly faced its share of significant challenges in 2008. While it remains true that the use of pharmaceutical preparations tends to increase in stressful times, the manufacturers themselves are held in check by the growing domestic and global economic crisis.

﻿Companies are subscribing more closely than ever before to the application of due diligence, and this certainly applies to their evaluation, selection, and purchase of developmental and manufacturing equipment. An ever-growing number of firms, both name brand and generic, are increasing the exploration and implementation of the concept of equipment standardization and are making more efficient use of existing assets as they make decisions to reduce the overall number of operating sites.

Many pharmaceutical equipment vendors have also felt the pinch as a result of the industry’s newfound reluctance to approve and spend capital. Tablet presses and related peripheral equipment represent one of the most critical investments that any developer of solid dose pharmaceutical products will make. Given the spending slowdown, and with users casting a more watchful eye upon equipment standardization, press vendors are engineering developmental solutions and features that greatly increase the likelihood of a successful handshake between research-specific designs and those intended to produce product in higher volumes. It is more important than ever for the press companies to demonstrate optimal flexibility with smaller units, as well as with other technologies that broaden the overall utilization capabilities of their equipment. The brief descriptions that follow will touch upon just a few of the more dynamic technologies that are being engineered and optimized by modern press manufacturers.Software, Single-Tablet Compaction

Lower punches in raised position during the sampling cycle.

Many tablet press manufacturers now offer a variety of research-based software packages and add-ons that facilitate the collection of useful data at the developmental stage. Going beyond the typical monitoring of preliminary and main compression and ejection forces, today’s systems for data retrieval and manipulation put greater power and versatility in the hands of the user. It is not at all uncommon for press research systems to allow for the measurement of upper and lower punch tightness, as well as the force required to remove a finished tablet from the die table surface via the take-off assembly.

Most of the data collected from the available research packages can be represented on an operator interface terminal both numerically and graphically; in most cases, it can be saved and downloaded in popular formats, including .xls and .pdf. While the power of each package varies from vendor to vendor, most of the more advanced modules place emphasis on the ability to create and analyze individual force profiles for many of the aforementioned parameters. When graphical compression force curves are created, for example, it is very useful to be able to superimpose the most recent one generated over previous curves measured at the same station on a press turret. The utility of such information can come in the form of determining how well (or poorly) a formulation compresses and whether or not there are content uniformity issues.

Some research systems also make provisions for the correlation of compression force data to other properties relating to the compression process, such as variable lubrication levels and optimal dwell times or peak compression times. Such ratios can then, in turn, provide valuable insight into key measurements affecting finished tablet criteria, including hardness, thickness, and friability.

There are also programs commercially available that create graphical representations of not only the amount of force required to compress a tablet but also the forces lost due to elasticity in the product itself and in the mechanical structure of the press. Ultimately, these graphs depict the net force that goes into compressing a tablet. Developmental personnel find this tool useful because it allows them to zero in on an optimal force, one that is substantial enough to produce a tablet to desirable specifications but not so significant as to damage the granules or cause premature wear on the press being utilized.When graphical compression force curves are created, for example, it is very useful to be able to superimpose the most recent one generated over previous curves measured at the same station on a press turret. The utility of such information can come in the form of determining how well (or poorly) a formulation compresses and whether or not there are content uniformity issues.

The ability to compress a single tablet on presses is not particularly novel. Pharmaceutical research personnel have been doing it for decades, typically on either a single-stroke machine with only one station or on a rotary press that has blank dies installed in all but one station. While both methods work in the most rudimentary sense, they fail to account for one physical phenomenon that is inescapable when developing product on a rotary press: centrifugal force.

Although its effects are largely speed-dependent, there certainly can be causality between centrifugal force and the ability to compress a product to a desired set of criteria. The key here, especially in the eye of the developer, should be how a product compresses at various turret speeds. Some press manufacturers now offer options that allow the user to make use of the single-station format on a rotary press more effectively.

Using only one station on the turret and filling the die cavity manually can tell the software the exact rotational speed at which the press should compress. The result is that in just one revolution, the turret can ramp up to the desired speed, compress and eject the tablet, and provide statistical data for analysis. This method not only increases the usefulness of collected data; it is also suitable for working with miniscule quantities of very expensive product.Multi-Layer Technology

Whether driven by marketing-based ideas, capacity requirements, or simple physics, there are always unique factors to consider when developing a sound procedure for a repeatable manufacturing process. Certain dosage forms can drive formulators and manufacturers to distraction, and multi-layer tablets often do. The challenges associated with multi-layer tablets are myriad. Issues with how well the different layers bind to one another, concerns with cross-contamination, and a need for optional modes of layer sampling are just a few. Fortunately, modern tablet press manufacturers continue to streamline the processes and options related to this form of compression.

The most common multi-layer dosage form is the double-layer, or bi-layer, product, followed by the triple-layer form. A number of press companies now offer small multi-layer machines that allow pharmaceutical manufacturers to make much more efficient use of valuable product as they work at the developmental stage. There are many reasons for choosing a multi-layer form over a more conventional mono-layer tablet. These can include the desire to keep sustained-release formulations separate from those that offer more immediate bioavailability, aesthetic appeal for consumers, and product line extension. Whatever the reason for gravitating to the form, reliable, desirable results are more easily achievable than ever before.

Developmental equipment for multi-layer use is available in a variety of forms. There are benchtop models and free-standing presses. Some presses offer a more conventional design that makes use of separate feeder assemblies for each granulation that goes into a multi-layer tablet, and there are alternative systems that use an indexing feed system for each layer. Multi-layer compression at this scale is typically most valuable as a study of compression feasibility.

Wash-in-place (WIP) and containment presses. With WIP systems, the bulk of the cleaning will be handled by the equipment, with minimal manual cleaning.

This type of compression can provide valuable insight into whether or not different layers bind together and the finished tablet offers the desired appearance, if that is deemed important. The potential drawback is that most developmental presses use turrets with a comparatively small pitch circle diameter. If dwell time is an important factor for finished tablet quality, then output is generally compromised.

New multi-layer presses at the larger scale definitely offer some distinct advantages, especially as pharmaceutical manufacturers adhere ever more closely to heightened quality. Many new presses offer features that are designed to mitigate the risk of compressing partial or single-layer tablets that may inadvertently make their way into a receptacle designated for acceptable tablets, especially during a first-layer sampling cycle.

Some press companies do this by moving the second-layer feeder back during this interval; some do so by physically moving the lower punches into a position during the sampling cycle in which their tips are almost flush with the die table surface as they pass under the feeder. The latter method ensures a "no-cavity" condition while at the same time reducing any risk associated with moving large components from their ideal set position. The sampling process itself has also been greatly optimized by some press manufacturers.

One new method makes use of a static sampling procedure in which the braking system on the machine stops the turret abruptly when a sample is called for. The turret moves slowly through the first-layer compression cycle, temporarily increasing the hardness so that the samples can be handled and tested, and then automatically returns to production settings. This method can be particularly advantageous, guaranteeing that the samples are filled in the same exact fashion as under production conditions and leading to more representative samples, less waste, and greater efficiencies.Dealing With Potent ProductsReflection NIR as integrated with a tablet press offers a very different approach than that offered by transmission NIR technology. Installed on a press, a reflection NIR system allows for 100% inspection of tablet product continuity and serves as an in-line tool that can essentially check and verify a product’s chemical fingerprint.

In recent years, the pharmaceutical industry has witnessed increasing numbers of potent products and compounds. The products themselves are becoming more powerful as formulators develop substances that are increasingly effective at providing desired physiological and therapeutic effects. Airborne particulate matter, more than many other substances, can represent a great risk to the equipment operator, particularly in cases in which a formulation contains a high percentage of a potent active drug substance. Historically, handling such compounds resulted in the use of positive-pressure respirators, full-body moon suits, and a variety of other types of personal protective equipment.

These issues led to a need for specifically engineered manufacturing equipment and systems that would offer far greater protection to individuals regularly working with potent compounds. Such systems would also, as a consequence of modern engineering capabilities, lead to the ability to clean the equipment more rapidly.

The marriage of these two issues has led to the creation by some press manufacturers of machines that combine high-containment features with those that fall under the banner of either wash-in-place (WIP) or clean-in-place (CIP). The generally accepted definition of WIP systems implies that the bulk of cleaning will be handled by the equipment itself, with minimal manual cleaning required to finish the process. CIP systems purportedly complete the entire cleaning process by themselves but in practice are often quite challenging to validate reliably.

Modern containment technology found on leading tablet presses will often make use of features—such as glove ports and rapid transfer ports—that allow the user to manipulate the press without breaching the integrity of containment prior to completing a batch (for example, stopping the press to examine or replace a faulty component or tool).

Press manufacturers now offer a variety of research-based software packages and add-ons that facilitate the collection of useful data to ensure quality.

Additionally, it is not uncommon to find features on a WIP/ containment machine that allow the user to gain access to the compression area via the glove ports and make use of manual spray and vacuum wands. These, too, are engineered so that containment is assured at all times during their use. The WIP or CIP systems typically utilize a system of sparging valves and balls for the delivery of various cleaning media, and all parts that come in contact with these materials are generally manufactured from stainless steel. Alternative containment systems include machines that make use of removable compression compartments.

When selecting this type of press, it is imperative to work closely with the chosen vendor to accurately identify all critical criteria, such as the expected occupational exposure limits (OELs), that the system is designed to maintain. Toxicology studies determine the levels of exposure to a given substance that can lead to adverse health-related effects. Often, specific OELs are established only by the company producing a given product and are generally created with the assumption that they apply to healthy adults over an eight-hour workday.

Some tablet press vendors are able to provide proof that they have subjected their containment technology to rigorous surrogate testing, while others are not. When evaluating contained equipment, the prospective buyer should always ask the vendor whether or not it has performed such testing and, provided the vendor has, if the buyer can have a copy of the test results. Companies that do offer this type of technology have, in most cases, applied it to machines across their capacity range, covering both developmental and production sizes.Analysis for Solid Dose Compression

Pharmaceutical manufacturers will always clamor for faster, more accurate methods of production with a goal of assuring their customers of better overall quality. Not long ago, many manufacturers were encouraged to begin closely evaluating what is known as PAT, or process analytical technology. First proposed by the United States Food and Drug Administration (FDA), PAT is defined by the FDA as "a system for designing, analyzing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes with the goal of ensuring final product quality." PAT is, therefore, essentially a framework under which a company develops faster, more accurate in- or on-line methodology for analyzing process results.

A major goal for any manufacturer today is to minimize, to the greatest possible degree, any risk of producing a product that does not meet stringent predefined parameters. Historically, mitigating this risk was achieved through the employment of rigorous end-of-process analytical work, which for a solid dosage form could include the measurement of weight, thickness, and hardness, as well as friability testing. While largely effective for ensuring that a quality product moves to the store shelves, these methods are perhaps not ideal for ensuring overall efficiencies. They are, after all, most often utilized after products are made, rather than during the production process.A major goal for any manufacturer today is to minimize, to the greatest possible degree, any risk of producing a product that does not meet stringent predefined parameters.

One emerging technology that shows the most promise when applied to in-process quality checking on a rotary tablet press makes use of near infrared (NIR) technology. NIR is a form of spectroscopy that utilizes light with a wavelength ranging from 800 to 2,500 nm. Molecular bands created by the use of NIR technology are typically very broad and therefore inherently complex, necessitating the employment of calibration techniques for multiple wavelengths. The technology is, however, very useful for different types of rapid analysis. Particular formulations will exhibit specific qualities when subjected to an NIR light source, creating a fingerprint that can later be used as a baseline for real-time quality analysis. Depending on the sample being analyzed, NIR light is generally measured in one of two ways, reflection or transmission.

Reflection NIR technology is a method in which light emitted from a source is reflected off of a sample and the resulting spectroscopy is read by an NIR sensor. Utilized on a high-speed rotary tablet press, this form of NIR measurement is suitable for 100% analysis due to its short cycle time. That very same speed, however, may limit the scope of its analytical potential to some degree.

The transmission method of NIR measurement occurs when light emitted from a source passes through a sample and is read by an appropriate sensor on the opposite side of the sample. While inherently slower than the reflection method, transmission can prove to be more accurate from a truly analytical perspective.

Following closely on the heels of the FDA’s suggestion that pharmaceutical manufacturers seriously consider the PAT initiative, some tablet press vendors soon embarked on various endeavors to create technologies embracing the opportunities presented by the use of NIR. It is important to note that some press vendors already offer potential solutions based on both forms of NIR measurement. Where the transmission method is desired, certain devices intended for the measurement of tablet weight, thickness, and hardness are fitted with an NIR measurement cell that can infer the percentage of active pharmaceutical ingredient (API) in finished tablet samples.

These devices deliver tablets chosen for NIR measurement in a rapid, highly controlled fashion, providing the user with comprehensive information about a tablet’s chemical and physical properties. Data recorded by the NIR cell is transferred to the user interface software for inclusion in summary batch reports; if necessary, the measured data can trigger in-process changes in the press for maintaining ideal product specifications.

Reflection NIR, as integrated with a tablet press, offers a very different approach than that offered by transmission NIR technology. Installed on a press, a reflection NIR system allows for 100% inspection of tablet product continuity and serves as an in-line tool that can essentially check and verify a product’s chemical fingerprint. Light information detected by the receiver can be compared to a baseline spectrum that is representative of that emitted by the product’s ideal composition when subjected to NIR radiation. The system allows for contact-free, non-destructive analysis of the content uniformity of active ingredients.

The modern tablet press market is extremely competitive, and the various manufacturers try hard to develop products that allow them to differentiate themselves from one another. Those who benefit the most from this competition are, of course, the end users. The leading press companies have made increasingly conscious efforts to engineer solutions in direct response to specific requests from their clients. Presses that allow a dizzying amount of flexibility for running a wide array of different products in highly variable quantities are now appearing on the market.

Much effort is focused on optimizing the safety and security of both the operator and the data generated by a machine, and the most reputable vendors offer more comprehensive assistance than ever before when it comes to the generation and customization of qualification documentation. Tablet presses play an integral role in modern pharmaceutical manufacturing, and their manufacturers seem poised to keep it that way.